Methods and compositions for lowering blood glucose levels using substituted pyridinium salts



United States Patent METHODS AND COMPOSITIONS FOR LOWERING BLOOD GLUCOSE LEVELS USING SUBSTITUTED PYRIDINIUM SALTS Victor John Bauer, Montvale, N.J., Gretchen Ellen Wiegand, Pearl River, N.Y., and Sidney Robert Safir, River Edge, N.J., assignors to American Cyanamid Company, Stamford, Conn, a corporation of Maine No Drawing. Filed Aug. 27, 1968, Ser. No. 755,721

Int. Cl. A61k 27/00 US. Cl. 424-263 Claims ABSTRACT OF THE DISCLOSURE Compositions containing furylpyridinium salts, thienylpyridinium salts and pyrrolylpyridinium salts are described. The use of these compositions as a means for the lowering of blood glucose levels in mammals is described.

DESCRIPTION OF THE INVENTION This invention relates to new compositions of matter. More particularly, it relates to compositions containing as an active ingredient a thienylpyridinium salt, a furylpyridinium salt, or a pyrrolylpyridinium salt and method of administering the same.

The active components of the new compositions may be illustrated by the following formula:

wherein R is selected from the group consisting of hydrogen, and lower alkyl; R is selected from the group consisting of lower alkyl, lower alkenyl, cycloalkyl(lower) alkyl, and lower alkoxy(lower)alkyl; Z is selected from the group consisting of a sulfur (S) atom, an oxyen (O) atom, and an NH group; and X is a pharmaceutically acceptable anion such as, for example, chloride, bromide, iodide, and the like. Illustrations of the active components of the present compositions and their activity in mammals are described hereinafter.

The above-described compounds which are active components of the compositions of this invention may be prepared by the reaction of a thienylpyridine, a furylpyridine, or a pyrrolylpyridine with a lower alkyl, lower alkenyl, cycloalky1(lower)alky1, or alkoxy(lower)alkyl halide at a temperature within the range of about 0 to 150 C. for a period of one minute to twenty-four hours with or without a solvent such as an alcohol or acetonitrile. The products which serve as active components are generally crystalline solids soluble in water. The reaction can be illustrated schematically as follows:

if, R

wherein R, R Z and X are as hereinbefore defined.

Among the compounds which are active components of the compositions of this invention are, for example: 1- methyl-4-(2-thienyl)pyridinium chloride, 1 allyl 4 (3- thienyl)pyridinium chloride, 1 (2 methoxyethyl)-4-(5- methyl-3-thienyl) pyridinium bromide, l-cyclopropylmethyl-4-(4-ethyl-2-thienyl)pyridinium bromide, 1-methyl-4- (3-furyl)pyridinium iodide, 1-propyl-4-(2-furyl)pyridinium bromide, 1-methallyl-4-(S-methyl-S-furyl)pyridinium chloride, 1-methyl-4-(2-pyrr0ly1)pyridinium iodide, 1- ethyl-4-(5-methyl-3-pyrrolyl)pyridinium bromide, and 1- (2-ethoxy-ethyl) -4- (5-methyl-2-pyrro1yl) pyridinium chloride.

The compounds which are active components of the compositions of this invention show hypoglycemic activity which indicates them to be useful as medicaments in the lowering of blood-sugar levels in mammals. When the compounds are administered orally to normal mice at doses of 0.1 to 0.5 millimole per kilogram, a reduction of blood-sugar levels is observed. These data, which are summarized in Table I, show that the compounds which are active components of the compositions of this invention are useful for the lowering of blood-sugar levels.

TABLE I.-DEOREASE IN BLOODGLUCOSE IN MICE AFTER ORAL ADMINISTRATION OF THIENYLPYRI- DINIUM, FURYLPYRIDINIUM, AND PYRROLYLPYRI- DINIUM SALTS The compositions of the present invention may be used to lower blood sugar levels in mammals at a dose of from 0.1 milligram to milligrams per kilogram of body weight per day. They may be administered in dosage units of from 5 mg. to 500 mg. per dose. Obviously, the unit dose may be taken in multiples or divided into a smaller dose.

The active components of this invention can be used with pharmaceutically acceptable carriers in compositions such as tablets, wherein the principal active ingredient is mixed with conventional tableting ingredients such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate, gums, and fractionally similar materials as pharmaceutical diluents or carriers. The tablets or pills of the novel compositions can be laminated or otherwise compounded to provide a dosage form aifording to advantage or prolonged or delayed action or predetermined successive action of the enclosed medication. For example, the tablet or pill can comprise an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former. The two components can be separated by an enteric layer which serves to resist disintegration in the stomach and permits the inner component to pass intact into the duodenum or to be delayed in release. A variety of materials can be used for such enteric layers of coatings, such materials including a number of polymeric acids or mixtures of polymeric acids with such materials. as shellac, shellac and cetyl alcohol, cellulose acetate and the like. A particularly advantageous enteric coating comprises a styrene maleic acid copolymer together with known materials contributing to the enteric properties of the coating. The term dosage form as described herein refers to physically discrete units suitable as unitary dosage for mammel sub jects, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect in association with the required pharmaceutical diluent, carrier or vehicle. Examples of suitable oral dosage forms in accord with this invention are tablets, capsules, pills, powder packets, granules, wafers, cachets, teaspoonfuls, dropperfuls, ampules, vials, segregated multiples of any of the foregoing and other forms as herein described.

3 DETAILED DESCRIPTION The present invention will be described in greater detail in the examples which follow which describe the preparation of thienylpyridinium, murylpyridinium, and pyrrolylpyridinium salts and formulations containing the active compounds.

EXAMPLE 1 Preparation of 4-(2-thienyl)pyridine A mixture of 2-thienylmagnesium bromide (prepared from 0.8 g. of magnesium and 5.0 g. of 2-bromothiophene), 35 ml. of ether, and 2.3 ml. of pyridine is heated at 160 C. in a bomb for 16 hours. The mixture is cooled, quenched with saturated aqueous ammonium chloride, and extracted with ether. The ether phase is dried over anhydrous magnesium sulfate and concentrated to a brown oil which is extracted with hexane. The hexane is distilled, and the solid residue is sublimed at 60 C./ mm. to provide a pale yellow solid. Recrystallization from hexane provides colorless plates, melting point 8788 C.

Example 2 Preparation of 1-methyl-4-(2-thienyl)pyridinium iodide A solution of 230 mg. of 4- (Z-thienyl) pyridine, 2.5 ml. of acetonitrile, and 500 mg. of methyl iodide is heated under reflux for 2 hours and then poured into 15 ml. of ether. The yellow solid which separates is collected and recrystallized from 2-propanol to provide yellow needles,

' melting point 181 C.

EXAMPLE 3 Preparation of 3-(4-pyridyl)thiophan-3-ol To a stirred suspension of 4-pyridyllithium (prepared from 40 ml. of 1.6 M butyllithium in hexane and 16 g. of 4-bromopyridine) in 450 ml. of ether is added at 30 C. 6.4 g. of 3-thiophanone in 50 ml. of ether. After 5 hours, the temperature is raised to C., and 3 N hydrochloric acid is added. The aqueous phase is separated, made basic with ammonium hydroxide and is extracted with ether and chloroform. The organic phase is dried over anhydrous magnesium sulfate and concentrated to dryness. The residue is triturated with ether to provide off- White crystals, melting point 123125 C.

EXAMPLE 4 Preparation of 4-(3-thienyl) pyridine A mixture of 3.8 g. of 3-(4-pyridyl) thiophan-3-ol, 1.5 g. of sulfur, and 1.5 g. of potassium bisulfate is fused at 225 C. for 1 hour, cooled, and treated with water. The mixture is made alkaline with sodium hydroxide and extracted with ether and chloroform. The organic phase is dried over anhydrous magnesium sulfate and concentrated to dryness. Partition chromatography of the solid residue provides pale yellow needles, melting point 135-138 C.

EXAMPLE 5 Preparation of 1-methyl-4-(3-thienyl)pyridinium iodide A solution of 2.0 g. of 4-(3-thienyl) pyridine, 5 ml. of methyl iodide, and 100 ml. of ethanol is heated under reflux for 2 hours. The solvent is distilled, and the solid residue is recrystallized from acetonitrile-ether to provide yellow crystals, melting point 176-177 C. (dec.).

EXAMPLE 6 Preparation of 1-allyl-4-(3-thienyl)pyridinium chloride A mixture of 0.6 g. of 4-(3-thienyl)pyridine and 2 ml. of allyl chloride is heated at 120 C. in a bomb for 18 hours. The excess allyl chloride is removed, and the solid residue is recrystallized from ethanol-ether to provide yel- 10w crystals, melting point 199201 C. (dec.).

4 EXAMPLE 7 Preparation of 1-cyclopropylmethyl-4- 3-thienyl) pyridinium bromide A mixture of 0.6 g. of 4-(3-thienyl)pyridine and 2 ml. of cyclopropylmethyl bromide is heated under reflux for 20 minutes. The resultant solid is collected and recrystallized from acetonitrile to provide yellow crystals, melting point 242243 C. (dec.).

EXAMPLE 8 Preparation of 1-(2-ethoxyethyl)-4-(3-thienyl) pyridinium chloride A mixture of 0.6 g. of 4-(3-thienyl)pyridine and 3 ml. of 2-chloroethyl ethyl ether is heated at 110 C. in a bomb for 18 hours. The excess chloroethyl ethyl ether is removed, and the solid residue is recrystallized from acetonitrile to provide off-white crystals, melting point 248 C. (dec.).

EXAMPLE 9 Preparation of 5-methyl-3-(4-pyridyl)thiophan-3-ol hydrochloride To a stirred suspension of 4-pyridyllithium (prepared from 40 ml. of 1.6 M butyllithium in hexane and 16 g. of 4-bromopyridine) in 450 ml. of ether is added at -30 7.3 g. of 5-methylthiophan-3-one in 50 ml. of ether. After 5 hours, the temperature is raised to 25 C., and 3 N hydrochloric acid is added. The aqueous phase is separated and made basic with ammonium hydroxide, and is extracted with chloroform. The chloroform solution is dried over anhydrous magnesium sulfate and concentrated to a dark oil. Evaporative distillation at 140 C./ 15 mm. gives a viscous yellow oil, which is dissolved in ethanolic hydrogen chloride. Addition of ether to the solution effects precipitation of an off-white solid, melting point 198200 C. (dec.).

EXAMPLE 10 Preparation of 4-(5-methyl-3-thienyl)pyridine A mixture of 0.5 g. of 5-methyl-3-(4-pyridyl)thiophen- 3-ol hydrochloride, 0.1 g. of sulfur, and 0.1 g. of potassium bisulfate is fused at 225 C., cooled, and treated with water. The mixture is made alkaline with sodium hydroxide and extracted with chloroform. The chloroform solution is dried over anhydrous magnesium sulfate and concentrated to a yellow solid. Silica gel chromatography followed by sublimation at C./ 12 mm. provides colorless needles, melting point -101 C.

EXAMPLE 11 Preparation of 1-methyl-4-(5-methyl-3-thienyl) pyridinium iodide A solution of 45 mg. of 4-(5-methyl*3-thienyl)pyridine, 1 ml. of methyl iodide, and 5 ml. of ethanol is heated under reflux for 2 hours. Addition of ether to the solution provides yellow crystals, melting point 197-200 C. (dec.).

EXAMPLE 12 Preparation of 3-(4-pyridyl)tetrahydrofuran-3-o1 hydrochloride To a stirred suspension of 4-pyridyllithium (prepared from 40 ml. of 1.6 M butyllithium in hexane and 16 g. of 4-bromopyridine) in 450 ml. of ether is added at 30 C. 5.4 g. of tetrahydrofuran-S-one in 50 ml. of ether. After 5 hours, the temperature is raised to 25 C. and 3 N hydrochloric acid is added. The aqueous phase is separated and made basic with ammonium hydroxide, and is extracted with chloroform. The chloroform solution is dried over anhydrous magnesium sulfate and concentrated to a brown oil. Evaporative distillation at C./ 12 mm. gives an oil which is dissolved in ethanolic hydrogen chloride. Addition of ether to the solution effects precipitation of an off-white solid, melting point 167l68 C. (dec.).

EXAMPLE 13 Preparation of 4-(3-furyl) pyridine EXAMPLE 14 Preparation of 1-methyl-4-(3-furyl)pyridinium iodide A solution of 250 mg. of 4-(3-furyl)pyridine, 3 ml. of methyl iodide, and 20 ml. of acetonitrile is heated under reflux for 2 hours. The solvent is removed and the solid residue is recrystallized from ethanol-ether to give yellow crystals, melting point 216-218 C.

EXAMPLE 15 Preparation of diethyl (2-isonicotinoyl-l-methylvinyl) aminomalonate A mixture of 7.7 g. of 4-acetoacetylpyridine, 10.6 g. of diethyl aminomalonate hydrochloride, 125 ml. of benzene, and 5 ml. of triethylamine is heated under reflux with stirring for 3.5 hours and is filtered. The filtrate is concentrated to an oily solid. Crystallization from 2-propanol provides colorless plates, melting point 9091 C.

EXAMPLE 16 Preparation of 4-(2-ethoxycarbonyl5-methyl-3-pyrrolyl) pyridine A mixture of 8.0 g. of diethyl (2-isonicotinoyl-1-methylvinyl)aminomal onate and 30 g. of polyphosphoric acid is heated at 90 C. for 30 minutes, quenched with water, and neutralized with sodium carbonate. The solid which separates is collected and recrystallized from ethanol to provide pale yellow crystals, melting point 165166 C.

EXAMPLE 17 Preparation of 4-(2-carboxy-5-methyl-3-pyrrolyl) pyridine A solution of 4. 5 g. of 4-(2-ethoxycarbonyl-5-methyl- 3-pyrrolyl)pyridine, 4.5 g. of sodium hydroxide, 40 ml. of ethanol, and 40 ml. of water is heated under reflux for 4 hours, concentrated to a volume of 60 ml. and acidified with acetic acid. A solid separates and is recrystallized from-ethanol-water to provide colorless crystals, melting point 214 C. (dec.).

EXAMPLE 18 Preparation of 4-(5-methyl-3-pyrrolyl)pyridine A 1.9 g. sample of 4-(2-carboxy-5-methyl-2-pyrrolyl) pyridine is heated at 180 C./15 mm. for 3 hours. The solid which sublimes is recrystallized from acetonitrile to provide colorless crystals, melting point 228-229 C. (dec.).

EXAMPLE 19 Preparation of 1-methyl-4-(5-methyl-3-pyrrolyl) pyridinium iodide A solution of 0.9 g. of 4-(5-methyl-3-pyrrolyl)pyridine, 0.7 ml. of methyl iodide, and ml. of acetonitrile is heated under reflux for 4 hours. Upon cooling to room temperature a solid separates, is collected, and recrystallized from acetonitrile to provide yellow needles, melting point 218 C. (dec.).

6 EXAMPLE 2.0

1-methyl-4-(2-thienyl)pyridinium iodide-5 g. Sodium carboxymethylcellulose 5% Aqueous solution q.s. cc.

The above solution contains approximately 5 mmole per cc.

EXAMPLE 21 The present compounds can be dispensed in dosage unit forms such as hard shell capsules or soft shell capsules. A formulation found useful in the preparation of such capsules is as follows:

Grams 1-methyl-4-(3-furyl)pyridinium iodide 2.0 Lactose, U.S.P. 300- Magnesium stearate (0.5%) 3.125

The formulation is thoroughly mixed and placed as equal quantities in 100 capsules.

EXAMPLE 22 dide 5.0 Corn starch 21.0 Methyl cellulose 400 35.0 Magnesium stearate 1% 18.2

Total 79.20

Make into 100 tablets. Each of the above tablets contains 50 mg. of drug.

EXAMPLE 23 The compounds of the present invention can also be given in the form of tablets containing other formulations as follows:

Grams 1-methyl-4-(S-methyl-S-thienyl)pyridinium iodine 50.0

Corn starch 300.0 Ethyl cellulose N 10 5 Magnesium stearate 1% 1.6

Total 356.6

Make into 1000 tablets. The above formulation can be varied by increasing or decreasing the corn starch and by the addition of other ingredients. Also, other disintegrating agents, such as potato starch, may be used in place of corn starch. Other lubricants such as stearic acid, talc and the like can be used. Sweetening agents such as saccharin or sodium cyclohexyl sulfarnate and flavoring such as peppermint oil, oil of Wintergreen, orange or cherry can be used.

We claim:

'1. The method of lowering blood glucose levels in mammals which comprises administering to said mammals a blood glucose lowering amount of a pyridinium salt of the formula:

consisting of sulfur, oxygen and NH and X is a pharmaceutically acceptable anion.

2. The method according to claim 1, in which the pyridinium salt is: 1-methyl-4-(2-thienyl)pyridinium iodide.

3. The method according to claim 1, in which the pyridinium salt is: 1-methyl-4-(3-thienyl)pyridinium iodide.

4. The method according to claim 1, in which the pyridinium salt is: l-allyl-4-(3-thienyl)pyridinium chloride.

5. The method according to claim 1, in which the pyridinium salt is: 1-cyc10propylmethyl-4-(3-thienyl)pyridinium bromide.

6. The method according to claim 1, in which the pyridinium salt is: l-(Z-ethoxyethyl)-4-(3-thienyl)pyridinium chloride.

7. The method according to claim 1, in which the pyridinium salt is: l-methyl-4-(5-methyl-3-thienyl)pyridinium chloride.

8. The method according to claim 1, in which the pyridinium salt is: l-methyl-4-(3-furyl)pyridinium iodide.

9. The method according to claim 1, in which the pyridinium salt is: 1-methy1-4-(5-methyl-3-pyrrolyl)pyridinium iodide.

10. A solid pharmaceutical composition in the form of a tablet, capsule or pill and in dosage unit form adapted 8 for administration to obtain a lowering of blood glucose levels in mammals comprising, per dosage unit, a blood glucose lowering-effective nontoxic amount within the range of from about 5 milligrams to 500 milligrams of at least one compound selected from the group consisting of a pyridinium salt of the formula:

N-Rl

wherein R is selected from the group consisting of hydrogen and lower alkyl; R is selected from the group consisting of lower alkyl, lower alkenyl, cyclopropyl(lower)alkyl and lower alkoxy (lower)alkyl; Z is selected from the group consisting of sulfur, oxygen and NH and X is a pharma ceutically acceptable anion and a solid pharmaceutically acceptable carrier.

References Cited FOREIGN PATENTS 875,887 8/1961 Great Britain.

JEROME D. GOLDBERG, Primary Examiner 

